The role of SoxE transcription factors in melanoma development

Abstract

Melanoma is a malignant type of skin cancer arising from the combined effects of genetic alteration and extrinsic signaling, resulting in transformation of neural crest (NC)-derived melanocytes into metastatic melanoma. Current therapies against metastatic melanoma are merely effective with less than 5% 5-year survival rate of patients. Understanding the underlying molecular mechanism of how melanoma acquires metastatic behavior could formulate strategies for new therapeutic options. Features of metastatic melanoma resemble NC cells undergoing an epithelial-mesenchymal transition (EMT) suggesting similar regulators might be in place to control the process. Our previous studies showed that SoxE transcription factors (Sox8/9/10) play a crucial role in NC development, in particular Sox9 transactivates expression of Snail2 and co-operates with it to induce features of EMT.

To examine the role of SOXE proteins in melanoma development and whether they regulate SNAIL expression, we first investigated the expression profile of SOXE and SNAIL in a human melanoma tissue array. The data showed that SOX8, SOX10, and SNAIL genes are highly expressed in metastatic melanoma whereas SOX9 and SNAIL2 transcript levels are low. Moreover, SNAIL transcript level was shown to have a positive correlation with SOX8 and SOX10 expression levels. SNAIL is well-known to be the key regulator of tumor invasiveness in various cancers. Our data raised the possibility that SOXE proteins may also regulate SNAIL expression in initiating melanoma metastatic behavior. The human metastatic melanoma cell line A375 exhibits similar SOXE and SNAIL expression profiles as the tissue array. Knockdown of SNAIL in A375 reduced its migratory ability and in vivo tumorigenecity, suggesting that SNAIL plays a crucial role in melanoma metastasis.

How SNAIL transcription is regulated in melanoma has been poorly understood. Previous studies have identified a minimal enhancer region downstream of the SNAIL locus which contains YY1 and SOX consensus binding sequences. Chromatin immunoprecipitation assay revealed that SOX8 and SOX10 proteins could bind to the SNAIL 3’ minimal enhancer region specifically. Mutation of the SOX consensus binding sequence reduced the enhancer activity while mutations in both SOX and YY1 binding sites resulted in further reduction suggesting that YY1 and SOX protein binding is required and important for enhancer activity and SNAIL transcription. These findings provide a molecular basis to examine further whether metastasis of melanoma is regulated by SOXE proteins in which one of the potential mechanisms could act through regulation of SNAIL expression.